The applicant, Deepak K Gupta, MD is an Instructor of Medicine in the Division of Cardiovascular Medicine at Vanderbilt University Medical Center. The applicant's goal is to become a leading independent cardiovascular investigator with a research program focused on understanding mechanisms for the development of hypertension and related sequelae, particularly heart failure. This application for a K23 Mentored Patient- Oriented Research Career Development Award describes an integrated and tailored plan for the principal investigator to acquire the skills and unique expertise needed to transition into an independent investigator, under the primary mentorship of Thomas J Wang MD. The didactic and research activities proposed center on the study of the natriuretic peptide system in African-Americans. Hypertension is the major contributor to the development of cardiovascular disease, especially among African- Americans. Salt-sensitivity is regarded as an important mechanism for the development of hypertension among African-Americans; therefore, understanding the origins of salt-sensitivity has biologic, preventive, and therapeutic importance. The natriuretic peptide system is the principal counter-regulatory mechanism to salt retention; however, little is known regarding racial differences in the natriuretic peptide system. In preliminary work, we found that African-Americans have lower levels of circulating natriuretic peptides compared with whites, which may be in part due to genetic variation. Therefore, we postulate that African-American individuals can have a relative natriuretic peptide deficiency, which predisposes to an impaired natriuretic peptide response to salt loading, increased salt-retention, and elevated blood pressure. The specific aims are (1) to assess the natriuretic peptide response to dietary salt loading in African-American individuals compared with white individuals, and (2) to examine the genetic basis for natriuretic peptide levels in African-Americans. During the course of the award period and through his study of the natriuretic peptide system in African- Americans, Dr. Gupta will acquire new expertise in 5 domains related to (1) patient-oriented physiologic studies, (2) pathophysiologic determinants of race-related differences in disease susceptibility, (3) genetic epidemiology, (4) the natriuretic peptide system, and (5) innovative techniques for measuring tissue sodium stores. The infrastructure at Vanderbilt for career development and scientific research is robust and uniquely capable of providing the resources that will promote the success of the proposed studies. Dr. Gupta's career development and research plans leverage his primary mentor's established record in human physiologic research related to the natriuretic peptide system. However, the targeted experiences will also provide a new direction for Dr. Gupta to develop into a leading investigator with unique expertise in the use of novel cardiac and non-cardiac imaging and circulating biomarkers for the study of hypertension and related sequelae, particularly in African-Americans. The results of the proposed studies will provide the basis for proposing and conducting new mechanistic and interventional studies in the next phase of the PI's career (i.e. R01) and therefore this Career Development Award would optimally prepare Dr. Gupta to lead his own independent clinical research program.